Epilepsy is a chronic neurological disorder presenting a wide spectrum of diseases that affects approximately 50 million people worldwide (Sander, 2003). Advances in the understanding of the body's internal ‘endocannabinoid’ system have lead to the suggestion that some cannabis-based medicines may have the potential to treat this disorder of hyperexcitability in the central nervous system (Mackie, 2006, Wingerchuk, 2004, Alger, 2006).
Cannabis has been ascribed both pro-convulsant (Brust et al., 1992) and anti-convulsant effects. Therefore, it remains to be determined whether cannabinoids represent a yet to be unmasked therapeutic anticonvulsant or, conversely, a potential risk factor to recreational and medicinal users of cannabis (Ferdinand et al., 2005).
In 1975 Consroe et al. described the case of young man whose standard treatment (phenobarbital and phenytoin), didn't control his seizures. When he began to smoke cannabis socially he had no seizures. However when he took only cannabis the seizures returned. They concluded that ‘marihuana may possess an anti-convulsant effect in human epilepsy’.
A study by Ng (1990) involved a larger population of 308 epileptic patients who had been admitted to hospital after their first seizure. They were compared to a control population of 294 patients who had not had seizures, and it was found that using cannabis seemed to reduce the likelihood of having a seizure. However this study was criticized in an Institute of Medicine report (1999) which claimed it was ‘weak’, as ‘the study did not include measures of health status prior to hospital admissions and differences in their health status might have influenced their drug use’ rather than the other way round.
In WO02/064109 reference is made to the anti epileptic effects of the cannabinoid cannabidiol (CBD).
WO 2006/054057 makes reference to the potential use of THCV to treat epilepsy amongst a range of diseases.
WO2009/007697 discloses formulations containing THCV and CBD.
Three controlled trials have investigated the anti-epilepsy potential of cannabidiol. In each, cannabidiol was given in oral form to sufferers of generalised grand mail or focal seizures.
Cunha et al (1980) reported a study on 16 grand mal patients who were not doing well on conventional medication. They received their regular medication and either 200-300 mg of cannabidiol or a placebo. Of the patients who received CBD, 3 showed complete improvement, 2 partial, 2 minor, while 1 remained unchanged. The only unwanted effect was mild sedation. Of the patients who received the placebo, 1 improved and 7 remained unchanged.
Ames (1986) reported a less successful study in which 12 epileptic patients were given 200-300 mg of cannabidiol per day, in addition to standard antiepileptic drugs. There seemed to be no significant improvement in seizure frequency.
Trembly et al (1990) reports an open trial with a single patient who was given 900-1200 mg of cannabidiol a day for 10 months. This trial showed seizure frequency was markedly reduced in the patient.
It is perhaps significant that some 20 years since these trials there has been no further development. This could be down to a number of factors including a general prejudice against medicines based on cannabis. It is also possible that the dose levels used in the trials were not optimal and the applicant has determined that cannabinoids may produce bell shaped dose response curves.
In addition to the disclosures suggesting CBD may be beneficial there is a report (Davis & Ramsey) of tetrahydrocanibinol (THC) being administered to 5 institutionalized children who were not responding to their standard treatment (phenobarbital and phenoytin). One became entirely free of seizures, one became almost completely free of seizures, and the other three did no worse than before.
However, there are more than forty recognisable types of epileptic syndrome partly due to seizure susceptibility varying from patient to patient (McCormick and Contreras, 2001, Lutz, 2004) and a challenge is finding drugs effective against these differing types.
Neuronal activity is a prerequisite for proper brain function. However, disturbing the excitatory-inhibitory equilibrium of neuronal activity may induce epileptic seizures. These epileptic seizures can be grouped into two basic categories: partial and generalised seizures. Partial seizures originate in specific brain regions and remain localised—most commonly the temporal lobes (containing the hippocampus), whereas generalised seizures appear in the entire forebrain as a secondary generalisation of a partial seizure (McCormick and Contreras, 2001, Lutz, 2004). This concept of partial and generalised seizure classification did not become common practice until the International League Against Epilepsy published a classification scheme of epileptic seizures in 1969 (Merlis, 1970, Gastaut, 1970, Dreifuss et al., 1981).
The International League Against Epilepsy further classified partial seizures, separating them into simple and complex, depending on the presence or the impairment of a consciousness state (Dreifuss et al., 1981).
The league also categorized generalised seizures into numerous clinical seizure types, some examples of which are outlined below:
Absence seizures occur frequently, having a sudden onset and interruption of ongoing activities. Additionally, speech is slowed or impeded with seizures lasting only a few seconds (Dreifuss et al., 1981).
Tonic-clonic seizures, often known as “grand mal”, are the most frequently encountered of the generalised seizures (Dreifuss et al., 1981). This generalised seizure type has two stages: tonic muscle contractions which then give way to a clonic stage of convulsive movements. The patient remains unconscious throughout the seizure and for a variable period of time afterwards.
Atonic seizures, known as “drop attacks”, are the result of sudden loss of muscle tone to either a specific muscle, muscle group or all muscles in the body (Dreifuss et al., 1981).
The onset of epileptic seizures can be life threatening with sufferers also experiencing long-term health implications (Lutz, 2004). These implications may take many forms:                mental health problems (e.g. prevention of normal glutamatergic synapse development in childhood);        cognitive deficits (e.g. diminishing ability of neuronal circuits in the hippocampus to learn and store memories);        morphological changes (e.g. selective loss of neurons in CA1 and CA3 regions of hippocampus in patients presenting mesial temporal lobe epilepsy as a result of excitotoxicity) (Swann, 2004, Avoli et al., 2005)        
It is noteworthy that epilepsy also greatly affects the lifestyle of the sufferer—potentially living in fear of consequential injury (e.g. head injury) resulting from a grand mal seizure or the inability to perform daily tasks or the inability to drive a car unless having had a lengthy seizure-free period (Fisher et al., 2000).
Three well-established and extensively used in vivo models of acute seizure, which mimic the neuronal activity and consequent physical symptoms that manifest in a seizure suffered by someone with epilepsy, are:                pentylenetetrazole-induced model of generalised seizures (Obay et al., 2007, Rauca et al., 2004);        pilocarpine-induced model of temporal lobe (i.e. hippocampus) seizures (Pereira et al., 2007); and        penicillin-induced model of partial seizures (Bostanci and Bagirici, 2006).These provide a range of seizure and epilepsy models, essential for therapeutic research in humans.        
It is an object of the present invention to identify phyto-cannabinoids or combinations of phyto-cannabinoids which have use in treating specific forms of seizure associated with epilepsy.
It is another object of the present invention to determine dose ranges which are likely to prove effective and identify combinations of cannabinoids (as might be present in different cannabis chemotypes or varieties) which are likely to prove more beneficial due to likely differences in their mechanisms of action.